Substituted xanthone carboxylic acid compounds

ABSTRACT

COMPOSITIONS CONTAINING AND METHODS EMPLOYING AS THE ESSENTIAL INGREDIENTS, NOVEL SUBSTITUTED XANTHONE CARBOXYLIC ACID COMPOUNDS WHICH ARE USEFUL AS INTERMEDIATES FOR PREPARING OTHER USEFUL XANTHONE CARBOXYLIC ACID COMPOUNDS, AND IN THE TREATMENT OF ALLERGIC CONDITIONS. METHODS FOR PREPARING THESE COMPOUNDS AND COMPOSITIONS AND INTERMEDIATES THEREIN ARE ALSO DISCLOSED. 7-(METHYLTHIO)-XANTHONE-2-CARBOXYLIC ACID IS ILLUSTRATED AS REPRESENTATIVE OF THE CLASS.

United States Patent (Mice 3,803,174 Patented Apr. 9, 1974 3,803,174SUBSTITUTED XANTHONE CARBOXYLIC ACID COMPOUNDS Jurg R. Pfister, LosAltos, and Ian T. Harrison and John H. Fried, Palo Alto, Calif.,assignors to Syntex (U.S.A.) Inc., Panama, Panama No Drawing. Filed Aug.23, 1971, Ser. No. 174,259 Int. Cl. C07d 7/44 US. Cl. 260-335 16 ClaimsABSTRACT OF THE DISCLOSURE Compositions containing and methods employingas the essential ingredient, novel substituted xanthone carboxylic acidcompounds which are useful as intermediates for preparing other usefulxanthone carboxylic acid compounds, and in the treatment of allergicconditions. Methods for preparing these compounds and compositions andintermediates therein are also disclosed.7-(methylthio)-xanthone-2-carboxylic acid is illustrated asrepresentative of the class.

The present invention is directed to novel substituted xanthonecarboxylic acid compounds useful as intermediates for the preparation ofother useful xanthone-Z-carboxylic acid compounds, and to compositionscontaining and methods utilizing these compounds as the essentialingredient in the treatment of symptoms associated with allergicmanifestations, for example, asthmatic conditions.

The present invention relates to novel -5 and C-7 mercapto and loweralkylthio substituted xanthone-Z-carboxylic acid compounds selected fromthose represented by the following formulas:

O O u R u C O OH h C O OH and the pharmaceutically acceptable, non-toxicesters, amides and salts thereof; wherein R is hydrogen or lower alkyl.

The compounds of the present invention, as defined by formulas (A) and(B) above, are useful as intermediates for the preparation of otherxanthone-Z-carboxylic acid compounds which, in turn, are useful in thetreatment of various allergic conditions. The process by which thecompounds of the present invention are useful for preparing the otheruseful xanthone-Z-carboxylic acid compounds is described in ourcopending application Ser. No. 174,261, filed on even date herewith andentitled Novel Substituted Xanthone Carboxylic Acid Compounds. Briefly,this process involves treating a 0-5 or C-7 (loweralkylthio)xanthone-2-carboxylic" acid or a lower alkyl ester thereof, ofthe present invention, and prepared herein from the corresponding (3-5or 0-7 mercaptoxanthone-2-carboxylic acid compounds, with:

(l) a peracid, such as peracetic acid and m-chloroperbenzoic, to givethe corresponding 0-5 or C-7 lower alkylsulfinylxanthone-Z-carboxylicacid compmuuds; or

(2) excess hydrogen peroxide to give the corresponding C-5 or 0-7 loweralkylsulfonylxanthone-Z-carboxylic acid compounds; or

treating a C-S or 0-7 mercaptoxanthone-Z-carboxylic acid, of the presentinvention, with chlorine under acidic conditions to give thecorresponding C-S or C-7 chlorosulfonylxanthone-Z-carboxylic acidcompounds followed by treatment of the latter with (a) base, such assodium hydroxide, to give the corresponding 0-5 or C-7sulfoxanthone-Z-carboxylic acid; or

(b) ammonia, monolower alkylamine, or dilower alkylamine to give thecorresponding 0-5 or C-7 sulfamoyl-, monolower alkylsulfamoyl-, anddilower alkylsulfamoylxanthone-Z-carboxylic acid compounds.

The compounds of the present invention are also useful for relievingsymptoms associated with allergic manifestations such as are broughtabout by antigen-antibody (allergic) reactions. In the relief of thesesymptoms, the method employing the compounds hereof serves to inhibitthe effects of the allergic reaction when administered in an effectiveamount. While not intending to be bound by any theoretical mechanism ofaction, the method hereof is believed to operate by inhibiting therelease and/or the action of toxic products, e.g. histamine,5hydroxytryptamine, slow releasing substance (SRS-A), and others, whichare produced as a result of a combination of specific antibody andantigen (allergic reaction). These properties make the subject compoundsparticularly useful in the treatment of various allergic conditions.

The present invention in a second aspect'thus relates to a method usefulfor inhibiting the effects of the allergic reaction which comprisesadministering an effective amount of a compound selected from thoserepresented by the following formulas:

and the pharmaceutically acceptable non-toxic esters, amides, and saltsthereof; wherein R is hydrogen or lower alkyl; or a pharmaceuticallyacceptable non-toxic composition incorporating said acids, esters,amides or salts as an essential ingredient.

The compounds of the present invention are also smooth muscle relaxants,e.g. bronchial dilators, and are therefore useful in the treatment ofconditions in which such agents may be indicated, as for instance in thetreatment of bronchioconstriction. The compounds of the presentinvention are also vasodilators and are therefore useful in thetreatment of conditions in which such agents may be indicated, as forinstance, in renal and cardiac disorders.

The present invention, in a third aspect, is directed to pharmaceuticalcompositions useful for inhibitingthe effects of the allergic reactioncomprising an effective amount of a compound selected from thoserepresented by the following formulas:

and the pharmaceutically acceptable esters, amides, and salts thereof;wherein R is hydrogen or lower alkyl; in admixture with apharmaceutically acceptable non-toxic carrier.

In the practice of the method of the present invention, an effectiveamount of a compound of the present invention or pharmaceuticalcompositions thereof, as defined above, is administered via any of theusual and acceptable methods known in the art, either singly or incombination with another compound or compounds of the present inventionor other pharmaceutical agents, such as antibiotics, hormonal agents,and so forth. These compounds or compositions can thus be administeredorally, topically, parenterally, or by inhalation and in the form ofeither solid, liquid, or gaseous dosages including tablets, suspensions,and aerosols, as discussed in more detail hereinafter. Theadministration can be conducted in single unit dosage form withcontinuous therapy or in single dose therapy ad libitum. In thepreferred embodiments, the method of the present invention is practicedwhen relief of symptoms is specifically required, or perhaps, imminent;however, the method hereof is also usefully practiced as continuous orprophylactic treatment.

In view of the foregoing as well as in consideration of the degree orseverity of the condition being treated, age of subject, and so forth,all of which factors being determinable by routine experimentation byone skilled in the art; the effective dosage in accordance herewith canvary over a wide range. Generally, an effective amount ranges from about0.005 to about 100 mg. per kg. of body weight per day and preferablyfrom about 0.01 to about 100 mg. per kg. of body Weight per day. Inalternate terms, an effective amount in accordance herewith generallyranges from about 0.5 to about 7000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids, or gases. .Thus, the compositions cantake the form of tablets, pills, capsules, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, and the like.The carriers can be selected from the various oils including those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly for injectable solutions. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, magnesium carbonate,magnesium stearate, sodium stearate, glyceryl monostearate, sodiumchloride, dried skim milk, glycerol, propylene glycol, water, ethanol,and the like. Suitable pharmaceutical carriers and their formulation aredescribed in Remingtons Pharmaceutical Sciences by E. W. Martin. Suchcompositions will, in any event, contain an effective amount of theactive compound together with a. suitable amount of carrier so as toprepare the proper dosage form for proper administration to the host.

The compounds of the present invention demonstrate activity asinhibitors of the effects of the allergic reaction as measured by testsindicative of such activity involving passive cutaneous anaphylaxis assubstantially described, for example, by J. Goose et al., Immunology,16, 749 (1969).

The compounds of the present invention can be prepared in accordancewith the following reaction sequence:

Sequence A --OOR' hal COOR 000B. Rm

(1) RO (200m (3) OOH COOH R'O R60 iJOOH (4) -oooan f oooa (RnzNo O oooruRou h s coon n s l o 0 ll 1 00m ooon we ms wherein each of R R and R islower alkyl, R and R being preferably methyl;

R is hydrogen or lower alkyl; and

halo is bromo, chloro, fluoro, or iodo, preferably bromo.

' With reference to the above reaction sequence, an ortho or parasubstituted (R phenol (2) is condensed with the1,3-dicarbo(lower)alkoxy-4-halobenzene Compound 1 in the presence ofcuprous oxide optionally in organic liquid reaction medium, preferablyan organic amide such as dimethyl acetamide, dimethyl formamide,N-methylpyrrolidine, tetramethylurea, and so forth, to prepare thecorresponding 1,3-dicarbo(lower)alkoxy-4-(oor p-substitutedphenyloXy)-benzene Compound 3.

The reaction is preferably conducted in an inert organic reactionmedium, such as those listed above, or suitable mixtures of one or moreof such medium. The reaction is further conducted at temperaturesranging from about to about 220 C., preferably from about to 200 C., andfor a period of time sufiicient to complete the reaction, ranging fromabout two hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of thesubstituted phenol per mole of the dicarbo- (lower)carboxyhalobenzeneper half mole of cuprous oxide. However, the amounts of the reactants tobe em ployed are not critical, some of the desired Compound 3 productbeing obtained when employing any proportions thereof. In the preferredembodiments, the reaction is conducted by reacting from about one toabout three moles of the substituted phenol compound with about from oneto about 1.2 moles and the dicarbo(lower) carboxyhalobenzene compound inthe presence of from about 0.5 to about 0.6 mole of the cuprous oxide.The inert organic reaction medium, if employed, is used in solventamounts.

Thereafter, the prepared Compound 3 is base hydrolyzed to give thecorresponding 1,3-dicarboxy-4-((oor p-substituted phenyloxy)benzene (4),The base hydrolysis conditions can be any employed conventionally in theart. Generally, the hydrolysis reaction is conducted using an alkalimetal hydroxide at about 50 to about 90 C. and for a period of timesufficient to complete the reaction, ranging from about 15 minutes toabout 60 minutes, preferably in the presence of inert organic reactionmedia such as those normally employed in organic chemical reactions ofthis type, e.g., aqueous alkanol solutions. Although two moles of baseare required per mole of Compound 3, the amounts employed are notcritical to produce the desired hydrolysis. Preferably from about threeto about five moles of base are employed per mole of Compound 3 and thereaction media, if employed, is used in solvent amounts.

The thus prepared diacid Compound 4 is then cyclized with phosphorylchloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or,preferably, polyphosphoric acid '(PPA), to give the corresponding 5- or7-substituted xanthone-Z-carboxylic acid Compound 5. The reaction ispreferably, but optionally, conducted in an inert organic reactionmedium including those usually employed in organic chemical reactions,such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth.The reaction is further conducted at temperatures ranging from about 60to about 180 C., and for a period of time sufficient to complete thereaction ranging from about 15 minutes to about 90 minutes.

Although the reaction consumes the reactants on the basis of one mole ofCompound 4 per mole of cyclizing reagent, the reaction can be performedusing any proportions of reactants. In the preferred embodiments,however, the reaction is conducted using from about 20 to about 50 molesof the cyclizing reagent per mole of starting Compound 4.

The 5- and 7-lower alkoxyxanthone-Z-carboxylic acid compounds (5; R=lower alkyl) thus prepared are converted to the respective 5- and7-hydroxy compounds (5; R =hydrogen) by treatment with hydrobromic orhydroiodic acid and acetic acid. This reaction is conducted at atemperature of from about 100 to about 160 C. The thus prepared 5- and7-hydroxy acid compounds are then esterified (R to give Compounds 6.This reaction is conducted with ethereal diazoalkane such asdiazomethane and diazoethane or with the desired lower alkyl iodide inthe presence of lithium carbonate at room temperature or with thedesired lower alkanol in the presence of a trace of sulfuric acid atreflux.

The hydroxy acid esters (6) are then treated with a dialkylthiocarbamoylchloride, such as dimethylthiocarbamoyl chloride, in the presence ofbase, such as an alkali metal hydride, and in organic liquid reactionmedia preferably an organic amide such as those listed above withrespect to reaction (1+2- 3) to afford the products (7). The reaction isconducted at temperatures ranging from about 20 to about 100 C.,preferably from 60 to about 80 C. and for a period of time sufficient tocomplete the reaction, ranging from about 1 hour to about 6 hours. Inthe preferred embodiments, the reaction is conducted by reaction of fromabout 1.1 to about 1.5 moles of dialkylthiocarbamoyl chloride per moleof Compound 6.

The product Compounds 7 are then rearranged by reaction at a temperatureof from about 200 to about 250 C., preferably from about 220 C. to about230 C., and for a period of time ranging from about 1 hour to about 8hours and in the presence of organic medium such as sulfolane,nitrobenzene, triethylene glycol and so forth, which is preferablyemployed in solvent amounts, to give Compound 8.

Compounds 8 are then converted to the corresponding 5- and 7-mercaptoacid Compounds 9 by base hydrolysis such as those described above forthe preparation of Compounds 4 from 3. The 5- and 7-lower alkyl thioether ester Compounds 10 are then prepared as described above (e.g., 56) or by reacting Compounds 9 with a lower alkyl halide in the presenceof base such as potassium carbonate and organic liquid reactions mediumsuch as those described above. The reaction is conducted at atemperature ranging from about 20 to about C., preferably from 50 toabout 60 C. and for a period of time sufficient to complete thereaction, ranging from about 2 hours to about 16 hours.

Hydrolysis of the ester (10), as described above (e.g. 3 4), affords the5- and 7-(loweralkylthio)-acid Compounds 11.

Alternatively, certain of the compounds of the present invention can beprepared in accordance with the followmg:

wherein R is lower alkyl.

With reference to above Sequence B, the alkylthiophenols (2') otherwisecorresponding to Compounds 2 are condensed with Compound 1', as abovedescribed, to give the alkylthio Compound 3'. This compound is thentreated as depicted and described above with reference to Sequence A togive the diacid Compound 4 and the (alkylthio)-xanthone-2-carboxylicacid (11').

An alternative method for the preparation of the intermediate 5- and7-hydroxy and -lower alkoxy Compounds 5 hereof is represented asfollows:

Sequence C C H 1 halo 3) wherein R and halo are as defined above.

With reference to Sequence C, an appropriate phenol (2) is treated with1,3-dimethy1-4-halo-(preferably iodo) (14) J30 OH benzene (12) asdescribed above, to prepare the corresponding1,3-dimethyl-4-phenyloxybenzene (13). This compound is then oxidizedsuch as with potassium permanganate in aqueous t-butanol, to give thecorresponding 1,3-dicarboxy-4-phenyloxybenzene (14). This compound isthen cyclized, as described above, to give the correspondingxanthone-Z-carboxylic acid (5) which can be treated as described above,to prepare the compounds of the present invention.

The acid esters of the xanthone-2-carboxylic acids hereof are preparedas described above (e.g., 5-) 6).

The amides of the xanthone-Z-carboxylic acids hereof are prepared bytreatment of the acids with thionyl chlo-' ride followed by treatmentwith anhydrous ammonia or lower alkyl or dilower alkyl amine.

The salts of the xanthone-Z-carboxylic acids hereof are prepared bytreating the corresponding acids with pharmaceutically acceptable base.Representative salts derived from such pharmaceutically acceptable basesinclude the sodium, potassium, lithium, ammonia, calcium, magnesium,ferrous, ferric, zinc, manganous, aluminum, manganic, trimethylamine,triethylamine, tri-propylamine, (dimethylamino)ethanol, triethanolamine,B-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine,hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, polyamineresins, caifeinc, procaine salts. The reaction is conducted in anaqueous solution, alone or in combination with an inert, Water miscibleorganic solvent, at a temperature of from about C. to about 100 C.,preferably at room temperature. Typical inert, water miscible organicsolvents include methanol, ethanol, isopropanol, butanol, acetone,dioxane, or tetrahydrofuran. When divalent metal salts are prepared,such as the calcium salts or magnesium salts of the acids the free acidstarting material is treated with about one molar equivalent ofpharmaceutically acceptable base. When the aluminimum salts of the acidsare prepared, about one molar equivalent of the pharmaceuticallyacceptable base are employed.

In the preferred embodiment of the present invention, the calcium saltsand magnesium salts of the acids are prepared by treating thecorresponding sodium or potassium salts of the acids with at least onemolar equivalent of calcium chloride or magnesium chloride,respectively, in an aqueous solution, alone or in combination with aninert water miscible organic solvent, at a temperature of from about 20C. to about 100 C.

In the preferred embodment of the present invention, the aluminum saltsof the acids are prepared by treating the acids with at least one molarequivalent of an aluminum alkoxide, such as aluminum triethoxide,aluminum tripropoxide and the like, in a hydrocarbon solvent, such asbenzene, xylene, cyclohexane, and the like at a temperature of from 20C. to about 115 C.

In the present specification and claims, by the term lower alkyl isintended a lower alkyl group containing 1 to 5 carbon atoms includingstraight and branched chain groups and cyclic alkyl groups, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,t-butyl, n-pentyl, isopentyl, sec.-pentyl, t-pentyl, cyclopropyl,cyclobutyl and cyclopentyl. By the term lower alkoxy" is intended thegroup O-lower alkyl" wherein lower alkyl is as defined above.

By the term pharmaceutically acceptable, non-toxic esters, amides, andsalts is respectively intended a lower alkyl ester, lower alkyl being asdefined above; an unsubstituted, mono(lower) alkyl, or (di)lower alkylsubstituted amide, lower alkyl being as defined above; and a salt asdefined above.

The nomenclature herein is employed in accordance with ChemicalAbstracts 5 6 Subject Index (1962, January- June).

The following examples illustrate the method by which the presentinvention can be practiced.

8 EXAMPLE 1 A mixture of 4.188 g. of l,3-dicarbomethoxy-4-bromobenzene,2.85 g. of p-methoxyphenol, 1.32 g. of cuprous oxide in 20 ml. ofdimethylacetamide is heated to 160 C. and maintained thereat withstirring and under a nitrogen atmosphere. After monitoring via t.l.c,indicates the reaction is substantially complete, the reaction mixtureis diluted with water and extracted with diethylether: methylenechloride (3:1). The extracts are chromato graphed on 150 g. of aluminaand the uniform fractions combined to give1,3-dicarbomethoxy-4-(p-methoxyphenyloxy)-benzene.

1,3-dicarbomethoxy 4 (p-methoxyphenyloxy)-benzene (3 g.) is combinedwith 150 ml. of 5% potassium hydroxide in methanol. The resultantmixture is refluxed for 1 hour after which time it is acidified, cooled,and filtered, to give 1,3-dicarboxy-4-(p-methoxyphenyloxy)-benzene.

Two grams of 1,3-dicarboxy-4-(p-methoxyphenyloxy)- benzene in 20 ml. ofconcentrated sulfuric acid is stirred at C. for 1 hour. After this time,the reaction mixture is poured into 200 ml. of ice water and theresultant mixture is heated on a steam bath for 15 minutes. The mixtureis cooled and filtered with the precipitate being washed with water andthen recrystallized from acetic acid to give7-methoxyxanthone-Z-carboxylic acid.

The foregoing procedure can be practiced using an alternativel,3-dicarboloweralkoxy-4-halo starting compound, such as1,3-dicarbomethoxy-4-chloro- (or iodo) benzene,1,3-dicarboethoxy-4-fluoro-benzene, 1,3-dicarboethoxy-4-bromobenzene,and the like, with similar results. Likewise, the foregoing procedurecan be practiced using an alternate 4-lower alkoxyphenol startingcompound to prepare the corresponding '7-loweralkoxyxanthone-2-carboxylic acids, e.g. 7-ethoxyxanthone-Z-carboxylicacid, 7 n-propoxyxanthone-2-carboxylic acid, 7isopropoxyxanthone-Z-carboxylic acid, 7-n-butoxyxanthone-2-carboxylicacid, 7-isobutoxyxanthone-2-carboxylic acid,7-sec-butoxyxanthone-Z-carboxylic acid, 7-t-butoxyxanthone-2-carboxylicacid, 7-n-pentyloxyxanthone-Z-carboxylic acid, and 7-cyclopentyloxyxanthone-Z-carboxylic acid.

Likewise prepared are the corresponding C-S substituted compounds, i.e.S-methoxyxanthone-Z-carboxylic acid, 5- ethoxyxanthone-Z-carboxylicacid, S-n-propoxyxanthone- Z-carboxylic acid, and so forth.

The foregoing procedure can also be practiced upon the corresponding4-(loweralkylthio)-phenol starting compounds to prepare thecorresponding C-5 and C-7 (lower alkylthio) substituted compounds, i.e.:

7- (methylthio)-xanthone-2-carboxylic acid,S-(methylthio)-xanthone-2-carboxylic acid,7-(ethylthio)-xanthone-2-carboxylic acid,S-(ethylthio)-xanthone-2-carboxylic acid,7-(n-propy1thio)-xanthone-2-carboxylic acid,S-(n-propylthio)-xanthone-2-carboxylic acid,7-(isopropylthio)-xanthone-2-carboxylic acid,S-(isopropylthio)-xanthone-2-carboxylic acid,7-(n-butylthio)-xanthone-2-carhoxylic acid,5-(n-butylthio)-xanthone-2-carboxylic acid,7-(isobutylthio-xanthone-2-'carboxy1ic acid,

5- (isobutylthio)-xanthone-2-carboxylic acid,7-(sec-butylthio)-xanthone-Z-canboxylic acid,S-(sec-butylthio)-xanthone-2-carboxylic acid, 7-(t-butylthio)-xanthone-2-carboxylic acid, 5-(t-butylthio-xanthone-Z-carboxylic acid,

7- (n-pentylthio)-xanthone-2-carboxylic acid,5-(n-pentylthio)-xanthone-2-carboxylic acid,7-(cyclopentylthio)-xanthone-2-carboxylic acid, andS-S-(cyclopenthylthio)-xanthone-2-carboxylic acid.

The cyclization reaction hereof can also be performed following theprocedure of Example 8.

9 EXAMPLE 2 The procedures of Example 1 are repeated usingo-hydroxyphenol and p-hydroxyphenol as starting compounds torespectively prepare hydroxyxanthone-Z-carboxylic acid and7-hydroxyzanthone-2-carboxylic acid.

Alternatively, the hydroxy compounds can be prepared from the loweralkoxy compounds of Example 1 according to the following representativeprocedure.

EXAMPLE 3 A mixture of 11 grams of 7-methoxyxanthone-2-carboxylic acidin 100 ml. of concentrated aqueous hydrogen iodide and 100 ml. of aceticacid is refluxed for 4 hours. After this time, the mixture is cooled,diluted with water, and filtered. The precipitate is washed and dried togive 7-hydroxyxanthone-Z-carboxylic acid.

EXAMPLE 4 A mixture of 4 grams of 7-hydroxyxanthone-2-carboxylic acid,g. of methyl iodide, and 10 g. of lithium carbonate in 50 ml. ofdimethylformamide is stirred at room temperature for a period of 16hours. After this period of time, the reaction mixture is poured intodilute hydrochloric acid-ice and the resultant mixture extracted withethyl acetate. The extracts are filtered through alumina to give methyl7 hydroxyxanthone-Z-carboxylate which can be recrystallized frommethanol.

EXAMPLE 5 To a solution of 6.2 g. of methyl 7-hydoxyxanthone-Z-carboxylate in 100 ml. of dimethylformamide are added 1 g. of sodiumhydride. The mixture is stirred for 10 minutes at room temperature undernitrogen. Dimethylthiocarbamoyl chloride (3 g.) is then added theretoand the resultant mixture stirred at 70 C. for 6 hours and then at roomtemperature for 16 hours. The mixture is then poured into 200 ml. ofwater containing 1 ml. of acetic acid, the resultant mixture is filteredand the solid dried to give methyl 7dimethylthiocarbamoyloxyxanthone-2-carboxylate.

Methyl 7-dimethylthiocarbamoyloxyxanthone-Z-carboxylate ((8 g.) in 150ml. of sulfolane is stirred at 230C. under nitrogen. After a total of 6hours under these conditions, t.l.c. indicates the absence of startingmaterial. The mixture is cooled to 80 C. and 150 ml. of hot water areslowly added. The mixture is then cooled and the filtered solid washedwith water and dried to give methyl7-(dimethylcarbamoylthio)xanthone-Z-carboxylate.

Methyl 7-(dimethylcarbarnoylthio)-xanthone-2-carboxylate (7.5 g.), 10 g.of potassium hydroxide and 250 ml. of 80% aqueous ethanol is refluxedfor 1 hour. After this time, 250 ml. of Water are added and the mixtureis treated wtih charcoal, filtered, acidified. The product is filteredoif and dried to give 7-mercaptoxanthone-2-carboxylic acid.

In like manner, 5-mercaptoxanthone-2-carboxylic acid. is prepared frommethyl S-hydoxyxanthone-2-carboxylate.

EXAMPLE 6 A mixture of 3 g. of 7-mercaptoxanthone-2-carboxylic acid in150 ml. of dimethylformamide, 5 ml. of methyl iodide and 5 ml. ofpotassium carbonate is stirred for 16 hours at 60 C. The mixture is thenpoured into dilute hydrochloric acid and the resultant mixture extractedwith ethyl acetate. The extracts are chromatographed on alumina(methylene chloride) to give methyl7-(methylthio)-xanthone-2-carboxylate (i.e. methyl7-thiomethoxyxanthone-Z-carboxylate) which can be recrystallized frommethylene chloride/ methanol.

A mixture of 580 mg. of methyl 7-(methylthio)-xanthone-Z-carboxylate, 30ml. of ethanol, 5 ml. of saturated sodium carbonate solution and 5 ml.of water is refluxed for 1 hour. The mixture is then cooled, acidifiedand the precipitate filtered oif to give 7-(methylthio)-xanthone-2-carboxylic acid (i. e. 7-thiomethoxyxanthone Z-carboxyl- 10 ic acid) asalso prepared in the alternative method described in Example 1.

A mixture of 0.8 g. of 7-mercaptoxanthone-2-carboxylic acid, 2 ml. of2-bromopropane, and excess potassium carbonate in 50 ml. ofdimethylformamide is stirred for 24 hours at 75 C. Dilute hydrochloricacid and ethanol are added, the solid filtered off and washed. The solidis saponified with sodium carbonate in aqueous methanol (30 minutesreflux). The alkaline solution is diluted with water, treated withcharcoal, filtered, and acidified to give7-(isopropylthio)-xanthone-2-carboxylic acid which can be recrystallizedfrom tetrahydrofuran/ethyl acetate.

In a similar manner (and alternative to the method of Example 1), thefollowing are prepared from the respective starting compounds:

EXAMPLE 7 A mixture of 51.5 g. of 1,3-dimethyl-4-iodobenzene (4-iodo-m-xylene), 40 g. of p-methoxyphenol, 16 g. of cuprous oxide in 300ml. of dimethylacetamide is heated to the boiling point and maintainedunder reflux (190 C.) for 144 hours with stirring and under a nitrogenatmosphere. The reaction mixture is then poured into ice water andextracted with ether and the extracts are filtered through 500 g. ofalumina in hexane to give 1,3-dimethyl 4- p-methoxyphenyloxy) -benzene.

A mixture of 41 g. of 1,3-dimethyl-4-(p-methoxyphenyloxy)-benzene, 300g. of potassium permanganate, 500 ml. of t-butanol, and 750 ml. of wateris heated to the boiling point and maintained thereat for a period of 3hours. After distilling ofi the t-butanol, the reaction mixture isfiltered, the clear filtrate acidified and the precipitate of 1,3dicarboxyl-4-(p-methoxyphenyloxy)-benzene is isolated by suctionfiltration and washed with water.

The 1,3 dicarboxy-4-(p-methoxyphenyloxy) benzene thus prepared is thencyclized as described in Example 1 or 8 hereof to give7-methoxyxanthone-2-carboxylic acid which can be converted to7-hydroxyxanthone-Z-carboxylic acid.

In a similar manner, the foregoing procedure can be practiced utilizingother p-lower alkoxyphenol or p-lower alkylthiophenol starting compoundsto prepare the corresponding products, for example,7-(methylthio)-xanthone-2-carboxylic acid, 7-ethoxyxanthone-2-carboxylicacid, 7-(ethylthio)-xanthone-2-carboxylic acid,7-n-propoxyxanthone-Z-carboxylic acid,7-(n-propylthio)-xanthone-Z-carboxylic acid,7-isopropoxyxanthone-Z-carboxylic acid,7-(isopropylthio)-xanthone-2-carboxylic acid and so forth, which caneach be converted to 7- hydroxyxanthone-2-carboxylic acid.

EXAMPLE 8 A mixture of 1,3-dimethyl-4-bromobenzene, 10.5 g. ofo-methoxyphenol, 4.65 g. of cuprous oxide, 40 ml. of tetramethylurea,and 75 ml. of N-methylpyrrolidone is stirred at for 96 hours. Theresultant mixture is diluted with water and extracted with methylenechloride. The methylene chloride extracts are chromatographed on 300 g.of alumina with gradient elution using hexanezether to give 1,3dimethyl-4-(o-methoxyphenyloxy) -benzene.

A mixture of 12 g. of 1,3-dimethyl-4-(o-methoxyphenyloxy)-benzene, 72 g.of potassium permanganate, 200 ml. of t-butanol and 350 ml. of water isrefluxed for 4 /2 hours. After this time, the t-butanol is distilledoff, and the reaction mixture is filtered. The filtrate is acidified togive 1,3-dicarboxy 4 (o-methoxyphenyloxy) benzene which can berecrystallized from benzenezheptane.

A mixture of 3 g. of 1,3-dicarboxy-4-(o-methoxyphenyloxy)-benzene, 75ml. of polyphosphoric acid, and 75 ml. of sulfol-ane is stirred at 125C. for a period of 2 hours. After this time, the reaction mixture ispoured into water, filtered and the precipitate washed. The precipitateis recrystallized from acetic acid (charcoal) to giveS-methoxyxanthone-Z-carboxylic acid which can be converted to5-hydroxyxanthone-2-carboxylic acid.

In a similar manner, the foregoing procedure can be practiced utilizingother o-lower alkoxy-phenol or o-lower alkylthiophenol startingcompounds to prepare the corresponding products, for example,5-(methylthio)-xanthone-2-carboxylic acid,S-ethoxyxanthone-Z-czrrboxylic acid, S-(ethylthio)-xanthone-2-carboxylicacid, S-n-propoxyxanthone-Z-carboxylic acid,5-(n-rpropylthio)-xanthone-2-carboxylic acid,5-isopropoxyxanthone-Z-carboxylic acid,5-(isopropylthio)-Xanthone-2-carboxylic acid, and so forth, which caneach be converted to 5- hydroxyxanthone-Z-carboxylic acid.

EXAMPLE 9 A mixture of 4.5 g. of 7-(methylthio)-xanthone-2-carboxylicacid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in 75 ml.of dimethylformamide is stirred at room temperature for a period of 18hours. After this period of time, the reaction mixture is poured intodilute hydrochloric acid-ice and the resultant precipitate is filteredoff and washed to give methyl 7-(meth ylthio)- xanthone-Z-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyliodides so as to prepare the corresponding lower alkyl acid estershereof, e.g. ethyl 7-(methy1- thio)-xanthone-2-carboxylate, n-propyl7-(methylthio)- xanthone-2-carboxylate, isopropyl7-(methylthio)-xanthone-Z-carboxylate, n-propyl 7-'(methylthio)xanthone-2-carboxylate, isobutyl 7-(methylthio)xanthone-2-carboxylate, sec-butyl7-(methylthio)-xanthone-2-carboxylate, t-butyl 7-(methylthio)xanthone2-carboxylate, npentyl 7-(methy1thio)-xanthone-2-carboxylate, and soforth.

In like manner, the other xanthone-Z-carboxylic acids hereof containingsubstituents at the C5 or C7 positions, prepared as described above, canbe converted to the corresponding acid esters, e.g. ethyl7-mercaptoxanthone-2-carboxylate (by use of one equivalent of lithiumcarbonate), ethyl S-(methylthio)-xanthone-2-carboxylate, methyl7-(isopropylthio)-xanthone-2-carboxylate, methylS-(isopropylthio)-xanthone-2-carboxylate, ethyl7-(isopropylthio)-xanthone-2-carboxylate, ethylS-(isopropylthio)-xanthone 2-carboxylate, and so forth.

EXAMPLE 10 To a solution of 10 g. of 7-(methylthio)-xanthone-2-carboxylic acid in 200 ml. of ethanol is added the theoretical amount ofsodium hydroxide dissolved in 200 ml. of 90% ethanol. The reactionmixture is then concentrated in vacuum to give sodium7-(methylthio)-xanthone 2- carboxylate.

In a similar manner, the potassium and lithium salts are prepared. Byreplacing the sodium salt by means of an appropriate metal salt reagent,e.g. calcium chloride, manganese chloride, and so forth, the otherxanthone-Z- carboxylic acid salts are prepared, e.g. magnesium 7-methylthio)-xanthone-2carboxylate, calcium7-(methylthio)-xanthone-2-carboxylate, aluminum 7-(methylthio)-xanthone-Z-carboxylate, ferrous 7- (methylthio)-xanthone- 2-carboxylate,zinc 7-(methylthio)-xanthone-2-carboxylate, manganese7-(methylthio)-xanthone 2-carboxylate, ferric7-(methylthio)-xanthone-2-carboxylate, and so forth.

In a similar manner, the xanthone-Z-carboxylic acid salts of the otherC-S or C7 substituted xanthone-Z- carboxylic acids hereof are prepared,e.g. potassium 5- mercaptoxanthone-Z-carboxylate, sodium7-(isopropylthio)-xanthone-2-carboxylate, sodium 5-(isopropy1thio)-xanthone-Z-carboxylate, and so forth.

EXAMPLE 1 1 To a mixture of 50 ml. of concentrated aqueous ammonia in500 ml. of methanol there are added 20 g. of 7-(ethylthio)-xanthone-2-carboxylic acid. The resultant mixture is stirredfor 2 hours and is then evaporated to dryness to give the ammonium saltof 7-(ethylthio)-xanthonc-2- carboxylic acid.

A solution of 10 g. of 7-ethylthioxanthone-Z-carboxylic acid in 50 ml.of thionyl chloride is heated at reflux for one hour. Thereafter, thesolution is evaporated to dryness to give the corresponding acidchloride to which is added a concentrated ethereal ammonia solution. Theresultant solution is evaporated giving 7-(ethylthio)-xanthone-2-carboxylic acid amide.

In like manner, the lower alkyl amides can be prepared usingmonoalkylamine or dialkylamine in lieu of ammonia in the aboveprocedures. Thus prepared, e.g. are 7-(methylthio)-xanthone-2-carboxylic acid amide, N-methyl7(n-propylthio)-xanthone-2-carboxylic acid amide, N,N- dimethyl5(methylthio)-xanthone 2 carboxylic acid amide, N,N-diethy17-(ethylthio)-xanthone-2Pcarboxylic acid amide, N-ethyl7-mercaptoxanthone-Z-carboxylic acid amide, N-n-propyl7-(isopropylthio)-xanthone-2- carboxylic acid amide, and so forth.

EXAMPLE 12 To a mixture of 20 g. of procaine and 500' ml. of aqueousmethanol are added 20 g. of 7-(methylthio)-xanthone- Z-carboxylic acid.The resultant mixture is stirred at room temperature for 16 hours. It isthen evaporated under reduced pressure, to give the procaine salt of7-(methylthio)-xanthone-2-carboxylic acid.

Similarly, the lysine, caffeine, and arginine salts thereof areobtained. In like manner, the e.g. procaine, lysine, caffeine, andarginine salts of the other 5- and 7-substituted xanthone-Z-carboxylicacids are obtained, e.g. the procaine salt of7-(ethylthio)-xanthone-2-carboxylic acid, the caffeine salt of5-(isopropylthio)-xanthone-2-carboxylic acid, the lysine salt of7-mercaptoxanthone-2-carboxylic acid, the procaine salt of5-(isopropylthio)-xanthone-2-car'boxylic acid, and the arginine saltof-7-(t-butylthio)-xanthone-2-carboxylic acid.

EXAMPLE 13 The following procedures illustrate the method by which thepharmaceutical compositions of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in ml. of a (9.47 g./l. water)sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00g./l. water) solution (20 ml.) is then added thereto. The resultantsolution having a pH of 7.38 is sterilized in an autoclave. This vehicleis then added to solid, dry 7-methylthioxanthone-2- carboxylic acid togive a preparation suitable for intravenous iniection containing 2.5 mg.of 7 methylthioxanthone-Z-carboxylic acid per ml. of total composition.

EXAMPLE 14 The following procedure illustrates a test procedure for thecompounds hereof.

Normal female (Sprague-Dawley) rats of to 200 grams each are passivelysensitized intradermally by injection of rat anti-egg albumin reaginicsera. After 24 hours, each rat is challenged intravenously with 1 ml. of0.5% Evans blue, 1 mg. egg albumin plus 0.20 mg. of7-methylthioxanthone-Z-carboxylic acid. Control rats receive no7-(methylthio)-xanthone-2-carboxylic acid. The dermal bluing is recorded15 to 25 minutes later. The rats which receive the7-(methylthio)-xanthone-2-carboxylic acid exhibit a 100 percentinhibition of allergic reaction whereas the control rats exhibit noinhibition.

The above procedure is repeated using -(methylthio)-xanthone-Z-carboxylic acid, with similar results. The above procedure isrepeated using oral admini'startion, with similar results.

Inhibition of reaginic antigen-antibody reactions in rats is regarded asrepresentative of inhibition of human reaginic allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent ofprovoked degree of asthma condition by changes in airway resistance onexpiration. The subject compounds are administered as an aerosol byinhalation before antigen challenge. Prevention of asthmatic conditionsupon the administration of the compounds is evidenced by a decrease inairway resistance and other, subjective improvements, e.g. reducedcough.

What is claimed is:

1. A compound selected from those represented by the following formulas:

-coon 5L -coon and the pharmaceutically acceptable, non-toxic loweralkyl esters, unsubstituted, mono(lower)alkyl, or di(lower) 1 4 alkylsubstituted amides and salts thereof; wherein R is hydrogen or loweralkyl.

2. The compound according to claim 1 of Formula 3. The compoundaccording to claim 2 wherein R is hydrogen.

4. The compound according to claim 2 wherein R is lower alkyl.

5. The compound according to claim 4 wherein R is methyl.

6. The compound according to claim 1 of Formula B.

7. The compound according to claim 6 wherein R is hydrogen.

8. The compound according to claim 6 wherein R is lower alkyl.

9. The compound according to claim 8 wherein R is methyl.

10. The acid compound according to claim 6 wherein R is hydrogen;7-mereaptoxantho ne-Z-carboxylic acid.

11. The acid compound according to claim 6 wherein R is methyl;7-(methylthio)-xanthone-2-carboxylic acid.

12. The acid compound according to claim 6 wherein R is ethyl;7-(ethylthio)-xanthone-2-carboxylic acid.

13. The acid compound according to claim 6 wherein R is n-propyl;7-(n-propylthio)-xanthone-Z-carboxylic acid.

14. The acid compound according to claim 6 wherein R is n-propyl;7-(n-propylthio)-xanthone-2-carboxylic acid.

15. The sodium salts of the compounds according to claim 1.

16. The salts according to claim 15 of Formula B.

References Cited UNITED STATES PATENTS 3,706,768 12/1912 Bays 260-335NORMA S. MILESTONE, Primary Examiner U.S. Cl. X-R. 424283

